Biased viruses make for good vaccines

Researchers use an aspect of basic cell metabolism to craft a virus that's …

There are a number of methods for generating immunity through vaccinations, but some of the most successful vaccines (such as smallpox and polio) have relied on live viruses, if only during the manufacturing process. As such, they carry a certain degree of risk, in that the combination of rare events and selective pressure can produce a dangerous virus. Yesterday's edition of Science contains a paper that describes a way of synthesizing a weakened virus that's much less prone to these potential dangers.

The idea behind the new work is based on a phenomenon called codon bias. A codon is a set of three RNA bases that encodes a single amino acid. Since there are 64 possible codons and only 20 amino acids, many amino acids are represented by multiple codons. For example, GCA, GCC, GCG, and GCT all code for the amino acid alanine. But a cell doesn't use them all equally; in humans, GCC is used four times as often as GCG. This codon bias extends to neighboring codons as well, as certain codon pairs are more common than others.

The bias has a subtle impact on protein translation, as the codons used most often are also used most efficiently. The differences may be small, but they can add up: the authors note that a typical protein that's 300 amino acids long can be encoded roughly 10151 ways, with some being translated far more efficiently than others.

This brings us back to the research at hand, which involves the polio virus. Simply working with the four proteins that form the structure of the mature virus, the authors were able to make 631 mutations that don't change the proteins produced, but leave the virus with its codons biased against it. When tested on cells, the virus was completely unable to reproduce. It wasn't a matter of the number of mutations; another construct with 566 mutations to favored codons reproduced just fine.

To make sure they had virus to work with, the authors made constructs with 224 and 407 mutations to unfavored codons. These viruses could reproduce and infect cells, but did so at an efficiency that was roughly one percent of that of the wild-type virus. Putting these weakened viruses into live mice caused no symptoms, but the mice developed immunity to otherwise lethal doses of normal poliovirus. In short, they worked nicely as vaccines.

Perhaps most significantly, the fact that hundreds of mutations contribute equally to the virus' poor replication, it's difficult for random mutation to produce all the mutations necessary for the virus to recover lethality; the authors sent it through 19 sets of fresh cells, and it never regained efficient infectivity. The authors describe the effect as "death by a thousand cuts," but also give the approach a more marketable name: synthetic attenuated virus engineering, or SAVE. Since, in principle, the approach could be used on any species of virus, there is almost certainly a market for it.